This invention provides a method for treating a subject with glaucoma by administrating a composition containing an agent or molecule which antagonize, inhibits, inactivates, reduce, suppresses, antagonizes, and/or limits the release, synthesis, or production from cells of TNF-xcex1 thereby treating the subject with glaucoma.
The cytokine known as tumor necrosis factor (TNF or TNF-xcex1) is structurally related to lymphotoxin. They have about 40 percent amino acid sequence homology (Old, Nature 330:602-603, 1987). These cytokines are released by macrophages, monocytes and natural killer cells and play a role in inflammatory and immunological events. The two cytokines cause a broad spectrum of effects both in vitro and in vivo, including: (i) vascular thrombosis and tumor necrosis; (ii) inflammation; (iii) activation of macrophages and neutrophils; (iv) leukocytosis; (v) apoptosis; and (vi) shock. TNF bas been associated with a variety of disease states including various forms of cancer, arthritis, psoriasis, endotoxic shock, sepsis, autoimmune diseases, infections, obesity, and cachexia. TNF appears to play a role in the three factors contributing to body weight control: intake, expenditure, and storage of energy (Rothwell, Int. J. Obesity 17:S98-S101, 1993).
Histopathologic studies of the glaucomatous optic nerve head in primary open angle glaucoma (POAG) reveal astroglial activation and tissue remodeling, which accompanies neuronal damage. As a part of tissue remodeling, backward bowing and disorganization of the laminar cribriform plates are common characteristics of glaucomatous eyes with either normal or high intraocular pressure.1 These histologic changes are accompanied by the upregulation of extracellular matrix components including collagen and proteoglycan, and adhesion molecules by optic nerve head astrocytes in glaucomatous eyes.2-6 The astoglial activation seen in glaucomatous optic nerve heads likely represents an attempt to limit the extent of the injury and promote the tissue repair process. However, despite the astroglial activation, there is limited deposition of extracellular matrix in glaucomatous optic nerve atrophy, which does not retain characteristics of scar tissue formation.7,8 This suggests that there are diverse cellular responses to the initial event or subsequent tissue injury, which preferentially results in tissue degradation.
In addition, reactive astrocytes following neuronal injury produce various neurotrophic factors and cytokines including TNF-xcex1.14 which play a critical role in the regulation of the synthesis of MMPs.15-17 Furthermore, the release of TNF-xcex1 from its membrane-bound precursor is a MMPs-dependent process.18 Matrix metalloproteinases (MMPs) are proteolytic enzymes that degrade components of extracellular matrix. Increased secretion of MMPs by activated glial cells have been implicated in various extracellular matrix remodeling events that occur during normal development and in a number of pathologies including atherosclerosis, arthritis, tumor growth, metastasis and glaucoma.9-13.
TNF-xcex1 is a potent immuno-mediator and pro-inflammatory cytokine that is rapidly upregulated in the brain after injury. It is also known as an inducer of apoptotic cell death via TNF-xcex1 receptor-1 occupancy (Hsu H, Xiong J, Goeddel DV. The TNF receptor 1-associated protein TRADD signals cell death and NF-kappa B activation. Cell. 1995;81:495-504.).
Open angle glaucoma (OAG) the second led cause of irreversible blindness in the United States, comprises 2 major syndromes: pi open angle glaucoma (POAG) and normal pressure glaucoma (NPG). POAG is a disease generally characterized by a clinical triad which consists of 1) elevated intraocular pressure (IOP); 2) the appearance of optic atrophy presumably resulting from elevated IOP; and 3) a progressive loss of peripheral visual sensitivity in the early stages of the disease, which may ultimately progress and impair central visual acuity. (Quigley, HA: Open angle glaucoma New Engl J Med 1993; 328:1097-1106.) Studies have indicated, however, that a surprisingly high percentage of patients with OAG have findings identical to those in POAG but with a singular exception; namely, that the IOP has never been demonstrated to be elevated. Several large population-based studies have documented the high prevalence of this form of glaucoma, often called xe2x80x9clow tension glaucomaxe2x80x9d (but more accurately called xe2x80x9cnormal pressure glaucomaxe2x80x9d) (NPG). The most conservative of these estimates place the percentage of glaucoma that occurs in the presence of xe2x80x9cnormalxe2x80x9d IOP at approximately 20-30% (Sommer A. Intraocular pressure and glaucoma Am J Ophthalmol. 1989;107:186-188. and Sommer A. Doyne Lecture, Glaucoma: Facts and Fancies. Eye 1996;10:295-301.)
In addition to the most common forms of glaucoma described above, there are secondary and closed angle forms of glaucoma which typically result in elevated intraocular pressure due to a variety of mechanisms. In virtually all these other forms of glaucoma, elevated eye pressure is found, and a characteristic optic neuropathy similar to that found in OAG ensues. If untreated, elevated intraocular pressure in these glaucomas invariably leads to visual loss and eventual blindness. In many forms of glaucoma, including those with normal intraocular pressure, lowering of intraocular pressure often fails to halt the progression of the disease. Comparison of glaucomatous progression between untreated patients with normal-tension glaucoma and patients with therapeutically reduced intraocular pressures. Collaborative Normal-Tension Glaucoma Study Group. Am J Ophthalmol. 1998 October; 126(4):487-97,)
Our previous studies (Wax M B, Tezel G, Edward D P. Clinical and histopathological findings of a patient with normal pressure glaucoma. Arch Ophthalmol. 1998;116:993-1001.) as well as others implicate that programmed cell death (i.e. apoptosis) underlies the death of retinal ganglion cells in glaucoma. Although glaucoma is a leading cause of blindness worldwide, neither the precise mechanism(s) of neuronal cell death nor effective strategies for treatment is known. However, several risk factors which increase the probability of developing glaucoma have been previously identified such as elevated intraocular pressure and ischemia, but there is no prior art that implies any role for the TNF family of proteins or receptors in the pathogenesis of glaucomatous opticneuropathy.
As described herein, it has been discovered that eyes with open angle glaucoma had increased expression of TNF-xcex1 and the TNF-xcex1 receptor-1 as demonstrated by immunohistochemistry in post mortem eyes. In addition, the in vitro experiments demonstrated that TNF-xcex1 secreted by human glial cells is increased in conditions which are thought to cause apoptosis in retinal ganglion cells such as ischemia and elevated hydrostatic pressure (which mimics elevated intraocular pressure in human glaucoma). Thus, TNF-xcex1 is a harmful and pathogenic to the human optic nerve in glaucomas. As provided herein, the invention provides a composition containing an agent or molecule which antagonize, inhibits, inactivates, reduce, suppresses, antagonizes, and/or limits the release, synthesis, or production from cells of TNF-xcex1. Such a composition is beneficial for the treatment of glaucoma.
This invention provides a method for beating a subject with glaucoma by administrating a composition containing an agent or molecule which antagonize, inhibits, inactivates, reduce, suppresses, antagonizes, and/or limits the release, synthesis, or production from cells of TNF-xcex1 thereby treating the subject with glaucoma.
In one embodiment, the compound or composition containing a molecule which suppresses the level or production of TNF-xcex1. In another embodiment, the compound or composition containing a molecule which inhibits the production of TNF-xcex1.
In another embodiment, the compound or composition containing a molecule which limits the synthesis or release of TNF-xcex1 from cells. In another embodiment, the compound is thalidomide. In another embodiment, the compound is a selective cytokine inhibitor. In another embodiment, the inhibitor is rolipram or phosphodiesterase 4 inhibitor.
In another embodiment the compound or composition containing a molecule which inactivated circulating TNF-xcex1. In another embodiment, the molecule is anti-TNF-xcex1 antibody. In another embodiment, the molecule is infliximab. In another embodiment, the molecule is recombinant TNF-xcex1 soluble receptors. In another embodiment, the molecule is etanercept.
This invention provides a TNF reducer which is hydrazine sulfate, pentoxifyline, ketotifen, tenidap, vesnarinone, cyclosporine, peptide T, sulfasalazine, those, antioxidants, corticosteroids, marijuana, glycyrrhizin, sho-saiko-to, L-carnitine, hyperthermia or hyperbaric oxygen therapy.
Lastly, this invention provides a method of assaying a subjects serum level of TNF-alpha as an indicator for treatment with TNF inhibitors. The assay measures the level of several cytokines in the serum of the subject such as interleukion 10 and interferon gamma.